U.S. patent application number 10/831091 was filed with the patent office on 2004-10-28 for plasticized stent coatings.
Invention is credited to Cheng, Peiwen, Udipi, Kishore.
Application Number | 20040215336 10/831091 |
Document ID | / |
Family ID | 32962783 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040215336 |
Kind Code |
A1 |
Udipi, Kishore ; et
al. |
October 28, 2004 |
Plasticized stent coatings
Abstract
The present invention provides a system for treating a vascular
condition, including a catheter, a stent with a stent framework
operably coupled to the catheter, and a drug-polymer coating on the
stent framework including at least one plasticizer dispersed within
the drug-polymer coating.
Inventors: |
Udipi, Kishore; (Santa Rosa,
CA) ; Cheng, Peiwen; (Santa Rosa, CA) |
Correspondence
Address: |
FRANK C. NICHOLAS
CARDINAL LAW GROUP
Suite 2000
1603 Orrington Avenue
Evanston
IL
60201
US
|
Family ID: |
32962783 |
Appl. No.: |
10/831091 |
Filed: |
April 23, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60465526 |
Apr 25, 2003 |
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Current U.S.
Class: |
623/1.42 ;
427/2.3 |
Current CPC
Class: |
A61L 2300/606 20130101;
A61L 31/16 20130101; A61L 29/085 20130101; A61L 29/16 20130101;
A61L 29/126 20130101; A61L 2300/608 20130101; A61L 31/141 20130101;
A61L 31/10 20130101; A61L 31/129 20130101 |
Class at
Publication: |
623/001.42 ;
427/002.3 |
International
Class: |
A61L 002/00 |
Claims
What is claimed is:
1. A system for treating a vascular condition, comprising: a
catheter; a stent operably coupled to the catheter, the stent
including a stent framework; and a drug-polymer coating operably
disposed on the stent framework, the drug-polymer coating including
at least one plasticizer dispersed within the drug-polymer
coating.
2. The system of claim 1 wherein the drug-polymer coating comprises
a bioactive agent to provide a therapeutic characteristic.
3. The system of claim 2 wherein the bioactive agent is selected
from the group consisting of antirestonotic agent, an
antineoplastic agent, an antiproliferative agent, an antisense
agent, an antiplatelet agent, an antithrombogenic agent, an
anticoagulant, an antibiotic, an anti-inflammatory agent, a gene
therapy agent, an organic drug, a pharmaceutical compound, a
recombinant DNA product, a recombinant RNA product, a collagen, a
collagenic derivative, a protein, a protein analog, a saccharide, a
saccharide derivative, and a combination thereof.
4. The system of claim 1 wherein the plasticizer comprises
lecithin.
5. The system of claim 1 wherein the plasticizer is selected from
the group consisting of dibutyl sebacate, citric acid, an alcohol
ester, polyethylene glycol, polypropylene glycol, a biostable
plasticizer, a biocompatible plasticizer, a biodegradable
plasticizer, and a combination thereof.
6. The system of claim 1 wherein the plasticized drug-polymer
coating has a thickness between 0.1 microns and 50 microns.
7. The system of claim 1 wherein the catheter includes a balloon
used to expand the stent.
8. The system of claim 1 wherein the catheter includes a sheath
that retracts to allow expansion of the stent.
9. The system of claim 1 wherein the stent framework comprises a
metallic base.
10. The system of claim 9 wherein the metallic base is selected
from the group consisting of stainless steel, nitinol, tantalum,
MP35N alloy, platinum, titanium, a suitable biocompatible alloy, a
suitable biocompatible material, and a combination thereof.
11. The system of claim 1 wherein the stent framework comprises a
polymeric base.
12. The system of claim 1 further comprising: an adhesion layer
positioned between the stent framework and the drug-polymer
coating.
13. The system of claim 12 wherein the adhesion layer comprises a
material selected from the group consisting of parylene,
polyurethane, phenoxy, epoxy, polyimide, polysulfone, pellathane, a
suitable polymeric adhesion material, and a combination
thereof.
14. The system of claim 12 wherein the adhesion layer has a
thickness between 0.1 microns and 2.0 microns.
15. The system of claim 1 further comprising: a barrier coating
covering the plasticized drug-polymer coating.
16. The system of claim 15 wherein the barrier coating is selected
from the group consisting of a polyurethane, a phenoxy, ethylene
vinyl acetate, polycaprolactone, polylactide, fibrin, collagen, a
biocompatible polymer, a biostable polymer, a biodegradable
polymer, and a combination thereof.
17. The system of claim 15 wherein the barrier coating has a
thickness between 0.1 microns and 10 microns.
18. A drug-polymer coated stent, comprising: a stent framework; and
a plasticized drug-polymer coating on the stent framework.
19. The drug-polymer coated stent of claim 18 wherein the
plasticized drug-polymer coating comprises a plasticizer selected
from the group consisting of lecithin, dibutyl sebacate, citric
acid, an alcohol ester, polyethylene glycol, polypropylene glycol,
a biostable plasticizer, a biocompatible plasticizer, a
biodegradable plasticizer, and a combination thereof.
20. The drug-polymer coated stent of claim 18 further comprising:
an adhesion layer positioned between the stent framework and the
drug-polymer coating.
21. The drug-polymer coated stent of claim 18 further comprising: a
barrier coating covering the plasticized drug-polymer coating.
22. A method of manufacturing a drug-polymer coated stent,
comprising: mixing a polymeric material with a solvent to form a
polymeric solution; interdispersing a plasticizer in the polymeric
solution to form a plasticized drug-polymer coating; applying the
plasticized drug-polymer coating onto a stent framework; and drying
the plasticized drug-polymer coating.
23. The method of claim 22 wherein the plasticizer is selected from
the group consisting of lecithin, dibutyl sebacate, citric acid, an
alcohol ester, polyethylene glycol, polypropylene glycol, a
biostable plasticizer, a biocompatible plasticizer, a biodegradable
plasticizer, and a combination thereof.
24. The method of claim 22 further comprising: applying an adhesion
layer onto the stent framework, wherein the adhesion layer is
applied prior to applying the plasticized drug-polymer coating.
25. The method of claim 24 wherein the adhesion layer comprises a
material selected from the group consisting of parylene,
polyurethane, phenoxy, epoxy, polyimide, polysulfone, pellathane, a
suitable polymeric adhesion material, and a combination
thereof.
26. The method of claim 22 further comprising: applying a barrier
coating onto the plasticized drug-polymer coating.
27. The method of claim 26 wherein the barrier coating is selected
from the group consisting of a polyurethane, a phenoxy, ethylene
vinyl acetate, polycaprolactone, polylactide, fibrin, collagen, a
biocompatible polymer, a biostable polymer, a biodegradable
polymer, and a combination thereof.
Description
RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application No. 60/465,526, "Plasticized Stent Coatings" to Kishore
Udipi and Peiwen Cheng, filed Apr. 25, 2003, the entirety of which
is incorporated by reference. FIELD OF THE INVENTION
[0002] This invention relates generally to biomedical stents. More
specifically, the invention relates to a drug-polymer coating with
a dispersed bioactive drug and at least one plasticizer on an
endovascular stent for in vivo, timed-release drug delivery.
BACKGROUND OF THE INVENTION
[0003] Drug-coated stents can improve the overall effectiveness of
angioplasty and stenotic procedures performed on the cardiovascular
system and other vessels within the body by delivering potent
therapeutic compounds at the point of infarction. Drugs such as
anti-inflammatants and anti-thrombogenics may be dispersed within
the drug-polymer coating and released in a controlled manner after
the insertion and deployment of a stent. These drugs and coatings
can reduce the trauma to the local tissue bed, aid in the healing
process, and significantly reduce the narrowing or constriction of
the blood vessel that can reoccur where the stent is placed.
[0004] Stenting procedures have had a major impact on the field of
interventional cardiology and endovascular surgery. Much medical
research and development in the last decade have been dedicated to
stents, and in the most recent years, to drug-eluting coatings for
stents. The efficacy of vascular stents is potentially increased by
the addition of stent coatings that contain pharmaceutical drugs.
These drugs may be released from the coating while in the body,
delivering their patent effects at the site where they are most
needed. Thus, the localized levels of the medications can be
elevated, and therefore potentially more effective than orally- or
intravenously-delivered drugs that distribute throughout the body,
the latter which may have little effect on the impacted area, or
which may be expelled rapidly from the body without achieving their
pharmaceutical intent. Furthermore, drugs released from tailored
stent coatings may have controlled, timed-release qualities,
eluting their bioactive agents over hours, weeks or even
months.
[0005] In practice, a common solvent or pair of solvents is used to
dissolve the drug and polymer. The polymer may include copolymers
or polymer blends. Then the drug-polymer solution is sprayed on the
stents. Upon drying, the drug-polymer is formed on the stent
surface. In this process, the drug-polymer ratio and polymer
content for each formulation are fixed.
[0006] When the drug-coated stent is deployed in a vessel in the
body, the drug release is predominantly based on a diffusion
mechanism. Drug diffusion is controlled in part by the molecular
size, the crystallinity, and the hydrophilic-lipophilic balance of
the drug, as well as the morphology of the polymeric coating, the
glass temperature Tg of the polymer and the polymer crystallinity.
For most drugs, there is a common releasing profile: a burst
release occurs where a large amount of drug gets released
initially, followed by a slow, gradual release that leads to a
gradually decaying effect where drug elution from the stent
diminishes with time. This typical releasing profile occurs because
of the resistance offered by the polymer film to the transport of
drug to the surface, and the reduction of the drug supply from
within the coating.
[0007] Several classes of drug-polymer chemistries have been
explored for use in stent coatings, as found in the current art. A
composition with a bioactive agent for coating the surface of a
medical device based on poly (alkyl)(meth)acrylate and
poly(ethyline-co-vinyl acetate) is described in "Bioactive Agent
Release Coating," Chudzik et al., U.S. Pat. No. 6,214,901, issued
Apr. 10, 2001. A composite polymer coating with a bioactive agent
and a barrier coating formed in situ by a low-energy plasma
polymerization of a monomer gas is described in U.S. Pat. No.
6,335,029, "Polymeric Coatings for Controlled Delivery of Active
Agents," K. R. Kamath et al., issued Jan. 1, 2002. Another
polymeric coating for an implantable medical article is presented
in "Implantable Medical Device," E. Koulik et al., U.S. Pat. No.
6,270,788, issued Aug. 7, 2001. This stent coating is based on
hydrophobic methacrylate and acrylate monomers, a functional
monomer having pendant chemically reactive amino groups capable of
forming covalent bonds with biologically active compounds, and a
hydrophilic monomer, wherein a biomolecule is coupled to the coated
surface. Use of block copolymers on a hydrophobic polymer substrate
is described in "Biocompatible Polymer Articles," E. Ruckenstein et
al., U.S. Pat. No. 4,929,510, issued May 29,1990.
[0008] In selecting polymers for drug delivery, three important
criteria must be met: polymer biocompatibility, satisfactory
mechanical properties such as durability and integrity during roll
down and expansion of the stent, and correct release profiles for
the drugs. Candidate chemistries for drug polymers may result in an
excessively rapid elution of an incorporated drug. When a drug is
eluted too quickly, it may be ineffective. When a drug is eluted
too slowly, the pharmaceutical intent may remain unfulfilled.
Furthermore, if insufficient drug is delivered after stent
deployment, the potential benefits of time-released drugs may be
compromised by inadequate dosages.
[0009] Unfortunately, some drug polymers do not provide the
mechanical flexibility necessary to be effectively used on a stent.
A stent may be deployed by self-expansion or balloon expansion,
accompanied by a high level of bending at portions of the stent
framework, which can cause cracking, flaking, peeling, or
delaminating of many candidate drug polymers while the stent
diameter is increased by threefold or more during expansion. The
candidate drug polymer may not stick or adhere. Furthermore, the
coating may fall off, crystallize or melt during preparation and
sterilization prior to deployment, further limiting the types of
drug polymers acceptable for use on cardiovascular stents.
[0010] It is desirable to have a medicated stent that can be
tailored to provide a desired elution rate profile for one or more
drugs, without compromising the mechanics of the stent during
deployment and use. A preferred drug-polymer system can be tailored
to accommodate a variety of drugs for controlled time delivery,
while maintaining mechanical integrity during stent deployment. Of
additional benefit is a polymeric system that can be readily
altered to control the elution rate of interdispersed bioactive
drugs and to control their bioavailability Furthermore, a more
desirable polymer-drug system can be tailored to enhance or
diminish the burst effect of drug delivery after stent deployment,
and to enhance the ability to deliver drugs over extended periods
of time.
[0011] It is an object of this invention, therefore, to provide a
framework and structure for effective, controlled delivery of
suitable quantities of pharmaceutical agents from medicated stents.
Additional objects of this invention include providing a system and
method for treating heart disease and other vascular conditions,
providing methods of manufacturing drug-polymer coated stents, and
overcoming the deficiencies and limitations described above.
SUMMARY OF THE INVENTION
[0012] One aspect of the invention provides a system for treating a
vascular condition, including a catheter, a stent including a stent
framework operably coupled to the catheter, and a drug-polymer
coating including at least one plasticizer operably disposed on the
stent framework.
[0013] Another aspect of the invention is a drug-polymer stent
comprising a stent framework and a plasticized drug-polymer coating
on the stent framework.
[0014] Another aspect of the invention is a method of manufacturing
a drug-polymer coated stent, including the steps of mixing a
polymeric material with a solvent to form a polymeric solution;
interdispersing a plasticizer in the polymeric solution to form a
plasticized drug-polymer coating; applying the plasticized
drug-polymer coating onto a stent framework, and drying the
plasticized drug-polymer coating.
[0015] The present invention is illustrated by the accompanying
drawings of various embodiments and the detailed description given
below. The drawings should not be taken to limit the invention to
the specific embodiments, but are for explanation and
understanding. The detailed description and drawings are merely
illustrative of the invention rather than limiting, the scope of
the invention being defined by the appended claims and equivalents
thereof. The foregoing aspects and other attendant advantages of
the present invention will become more readily appreciated by the
detailed description taken in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is an illustration of a system for treating a
vascular condition including a catheter, a stent coupled to the
catheter, and a drug-polymer coating including at least one
plasticizer, in accordance with one embodiment of the current
invention;
[0017] FIG. 2 is a cross-sectional view of a drug-polymer coated
stent, in accordance with one embodiment of the current
invention;
[0018] FIG. 3 is a schematic illustration of a drug-polymer coating
with at least one plasticizer interdispersed within the
drug-polymer coating, in accordance with one embodiment of the
current invention;
[0019] FIG. 4 is a graphical illustration of drug elution from a
drug-polymer coated stent including at least one plasticizer, in
accordance with one embodiment of the current invention; and
[0020] FIG. 5 is a flow diagram of a method of manufacturing a
drug-polymer coated stent, in accordance with one embodiment of the
current invention.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0021] FIG. 1 shows an illustration of a system for treating a
vascular condition including a catheter 110, a stent including a
stent framework 120 coupled to the catheter, and a drug-polymer
coating 130 on stent framework 120, the drug-polymer coating
including at least one plasticizer dispersed within the
drug-polymer coating, in accordance with one embodiment of the
present invention at 100. The plasticizers within the drug-polymer
coating modulate the release of incorporated drugs from the
coatings. The system may be used in the treatment of heart disease,
various cardiovascular ailments, and other vascular conditions
using catheter-deployed endovascular stents with plasticized
drug-polymer coatings and other polymer coatings disposed on the
stent frameworks for controlling the release and phasing of
bioactive agents and drugs from the drug polymer. Treating vascular
conditions refers to the prevention or correction of various
ailments and deficiencies associated with the cardiovascular
system, urinogenital systems, biliary conduits, abdominal
passageways and other biological vessels within the body using
stenting procedures.
[0022] Speeding the transport of drug from the inner layers of the
drug-polymer coating 130 to the outer edge is accomplished through
the addition of suitable plasticizers into the drug polymer.
Plasticizers are small, bulky molecules that can improve the
flexibility of polymeric materials, and also allow more drugs to be
loaded in the drug-polymer. The plasticizers have good
compatibility with the polymer but not so much as to have a solvent
effect. This optimum compatibility helps to retain the plasticizer
in the film and not to exude. These small, bulky molecules tend to
separate the polymer chains from each other and reduce the cohesive
force, thereby making the polymer coating more flexible. Separating
polymer chains, in addition to flexibilizing the coatings, also
facilitates the transport of the drug from the inner layers to the
outer layers. Drugs located near the outer surface of the
drug-polymer coating tend to be eluted first, whereas drugs nearer
the stent framework are exuded later. Since drugs nearer the stent
framework have an effectively thicker polymer layer to diffuse
through before the drug leaves the coating, the elution rate tends
to be slower. Additionally, since the diffusion process is driven
in part by the concentration of the drugs in the drug polymer, the
elution rate will naturally tend to be reduced as the concentration
of drugs diminishes and as the amount of drug in the drug polymer
lessens. Adding plasticizers, particularly to the inner layers of
the drug polymer, can help in overcoming the burst effect and in
maintaining a steady and more controlled release profile.
[0023] In this embodiment, catheter 110 may include a balloon used
to expand the stent, or a sheath that retracts to allow expansion
of the stent. Drug-polymer coating 130 includes one or more
bioactive agents that provide a therapeutic characteristic. The
bioactive agent is a pharmacologically active drug or bioactive
compound. Drug-polymer coating 130 may include another polymer
layer such as a cap coating or barrier coating, or another drug
polymer. The polymer layer provides a controlled drug-elution
characteristic for each bioactive agent or drug. Drug elution
refers to the transfer of the bioactive agent out from drug polymer
coating 130. Drug elution is determined as the total amount of
bioactive agent excreted out of the drug polymer, typically
measured in units of weight such as micrograms, or in weight per
peripheral area of the stent. In one embodiment, the drug polymer
includes between 0.5 percent and 50 percent of the bioactive agent
of drug by weight.
[0024] Upon insertion of catheter 110 and stent framework 120 with
drug-polymer coating 130 into a directed vascular region of a human
body, stent framework 120 may be expanded by applying pressure to a
balloon positioned inside the stent, or by retracting a sheath to
allow expansion of a self-expanding stent. Balloon deployment of
stents and self-expanding stents are well known in the art.
[0025] Stent framework 120 is typically oriented cylindrically such
that an exterior surface of the stent framework contacts the vessel
wall when deployed in the body, and an interior surface of the
stent framework is in contact with the blood or other bodily fluids
flowing through the vessel. Stent framework 120 may comprise a
metallic base or a polymeric base. The metallic base may comprise a
material such as stainless steel, nitinol, tantalum, MP35N alloy,
platinum, titanium, a suitable biocompatible alloy, or any
combination thereof. Stent framework 120 may comprise any suitable
biocompatible polymer.
[0026] Drug-polymer coating 130 includes one or more bioactive
drugs or agents to provide a therapeutic characteristic. The
bioactive agents provide treatment or prevention of one or more
conditions including coronary restenosis, cardiovascular
restenosis, angiographic restenosis, arteriosclerosis, hyperplasia,
and other diseases and conditions. For example, the bioactive agent
can be selected to inhibit or prevent vascular restenosis, a
condition corresponding to a narrowing or constriction of the
diameter of the bodily lumen where the stent is placed. In one
embodiment, the bioactive drug comprises an antirestenotic agent
such as rapamycin, a macrolide antibiotic that possesses
immuno-suppressant activity. In another embodiment, the bioactive
drug comprises a bioactive agent such as an antisense agent,
antirestonotic agent, an antineoplastic agent, an antiproliferative
agent, an antithrombogenic agent, an anticoagulant, an antiplatelet
agent, an antibiotic, an anti-inflammatory agent, a steroid, a gene
therapy agent, a therapeutic substance, an organic drug, a
pharmaceutical compound, a recombinant DNA product, a recombinant
RNA product, a collagen, a collagenic derivative, a protein, a
protein analog, a saccharide, and a saccharide derivative. In
another embodiment, drug-polymer coating 130 includes a combination
of bioactive agents. For example, a first bioactive drug may
comprise an antirestenotic drug such as rapamycin or a rapamycin
derivative, and a second bioactive drug may comprise an
anti-inflammatory drug such as dexamethosone.
[0027] Drug-polymer coating 130 is positioned on stent framework
120. Various drugs are loaded into drug-polymer coating 130 on
stent framework 120. Different types of drugs and polymers may be
included in drug-polymer coating 130, for example, for release of
drugs at various stages of restenosis. In one embodiment, the
drug-polymer coated stent comprises a drug-polymer coating 130
where drug polymers are deposited in layers. Optionally, polymer
membranes or barrier layers may be positioned in between the
drug-polymer layers for controlled release of various drugs. Drugs
such as anti-proliferatives, anti-inflammatants, anti-thrombotic
drugs, antisense drugs, gene therapies and therapeutic peptides can
be loaded on the stent for delivery during the different stages of
the restenotic process. The drugs in the form of drug polymers may
be deposited in layers with polymer membranes in between for
controlled release. Drugs in the form of microspheres, powders, and
other forms may also be positioned in the drug-polymer coating.
Applications of the drug-polymer stent include restenotic
treatments of coronary blood vessels after balloon angioplasty and
stenting, treatment of in-stent hyperplasia, and local drug
delivery to blood vessel walls.
[0028] A cap coating or barrier coating may be positioned on
drug-polymer coating 130. The barrier coating also can be used for
the delivery of drugs. For example, an antithrombotic drug such as
hirudin or heparin can be incorporated into the outer polymer
membrane for the prevention of acute thrombosis. The barrier
coating may cover a portion or the entire stent framework in
addition to drug-polymer coating 130. An adhesion layer may be
positioned between stent framework 120 and drug-polymer coating 130
to assist in adhesion between stent framework 120 and drug-polymer
coating 130.
[0029] FIG. 2 shows a cross-sectional view of a drug-polymer coated
stent in accordance with one embodiment of the current invention at
200. Drug-polymer coated stent 200 comprises a stent framework 220
and a plasticized drug-polymer coating 230 operably disposed on
stent framework 220. Drug-polymer coated stent 200 may also include
an adhesion layer 232, additional drug-polymer layers, and a cap or
barrier coating 234.
[0030] Stent framework 220 may comprise a metallic base or a
polymeric base. The base may comprise, for example, stainless
steel, nitinol, tantalum, MP35N alloy, platinum, titanium, a
suitable biocompatible alloy, a suitable biocompatible material, a
suitable polymeric material, or a combination thereof.
[0031] Drug-polymer coating 230 is operably disposed on the stent
framework. The drug-polymer coating includes at least one bioactive
agent to provide a therapeutic characteristic. Drug-polymer coating
230 includes at least one plasticizer.
[0032] The bioactive agent within drug-polymer coating 230 may
include, for example, antirestonotic agent, an antineoplastic
agent, an antiproliferative agent, an antisense agent, an
antiplatelet agent, an antithrombogenic agent, an anticoagulant, an
antibiotic, an anti-inflammatory agent, a gene therapy agent, an
organic drug, a pharmaceutical compound, a recombinant DNA product,
a recombinant RNA product, a collagen, a collagenic derivative, a
protein, a protein analog, a saccharide, a saccharide derivative,
or a combination thereof. For example, an antirestenotic agent such
as rapamycin or rapamycin derivatives prevents or reduces the
recurrence of narrowing and blockage of the bodily vessel. An
antisense drug works at the genetic level to interrupt the process
by which disease-causing proteins are produced. An antineoplastic
agent is typically used to prevent, kill, or block the growth and
spread of cancer cells in the vicinity of the stent. An
antiproliferative agent may prevent or stop targeted cells or cell
types from growing. An antithrombogenic agent actively retards
blood clot formation. An anticoagulant often delays or prevents
blood coagulation with anticoagulant therapy, using compounds such
as heparin and coumarins. An antiplatelet agent may be used to act
upon blood platelets, inhibiting their function in blood
coagulation. An antibiotic is frequently employed to kill or
inhibit the growth of microorganisms and to combat disease and
infection. An anti-inflammatory agent such as dexamethasone can be
used to counteract or reduce inflammation in the vicinity of the
stent. At times, a steroid is used to reduce scar tissue in
proximity to an implanted stent. A gene therapy agent may be
capable of changing the expression of a person's genes to treat,
cure or ultimately prevent disease.
[0033] By definition, a bioactive agent is any therapeutic
substance that provides prevention or treatment of disease or
disorders. An organic drug is any small-molecule therapeutic
material. A pharmaceutical compound is any compound that provides a
therapeutic effect. A recombinant DNA product or a recombinant RNA
product includes altered DNA or RNA genetic material. Bioactive
agents of pharmaceutical value may also include collagen and other
proteins, saccharides, and their derivatives. The molecular weight
of the bioactive agent typically ranges from 200 to 60,000 Dalton
and above.
[0034] Drug-polymer coating 230 includes at least one plasticizer.
The plasticizer tends to separate the polymeric chains, which may
add more flexibility to the drug-polymer coating, allow more drugs
to be contained in the drug polymer, and aid in the control of the
diffusion of the drugs from the interior of the drug-polymer to the
outside surface, where it is eluded into the surrounding tissue and
fluids. The plasticizer may include, for example, lecithin, dibutyl
sebacate, citric acid, an alcohol ester, polyethylene glycol,
polypropylene glycol, a biostable plasticizer, a biocompatible
plasticizer, a biodegradable plasticizer, or a combination thereof.
The plasticized drug-polymer coating typically has a thickness
between 0.1 microns and 50 microns. Drug-polymer coating 230 covers
at least a portion of stent framework 220.
[0035] Drug-polymer coated stent 200 may also include an adhesion
layer 232, which is positioned between stent framework 220 and
drug-polymer coating 230. The adhesion layer enhances the bond
strength between the drug-polymer coating and the stent framework,
particularly with metallic stent frameworks. Adhesion layer 232
comprises a material such as, for example, parylene, polyurethane,
phenoxy, epoxy, polyimide, polysulfone, pellathane, a suitable
polymeric adhesion material, or a combination thereof. The adhesion
layer typically has a thickness between 0.1 microns and about 2.0
microns. Adhesion layer 232 may cover all or a portion of stent
framework 220.
[0036] Drug-polymer coated stent 200 may also include barrier
coating 234, sometimes referred to as a cap coating, which covers
the plasticized drug-polymer coating. Barrier coating 234 is
typically a polymeric membrane and aids in the control of the
elution of drugs from the drug-polymer coating. Barrier coating 234
may include, for example, a polyurethane, a phenoxy, ethylene vinyl
acetate, polycaprolactone, polylactide, fibrin, collagen, a
biocompatible polymer, a biostable polymer, a biodegradable
polymer, or a combination thereof. The barrier coating has a
thickness typically between 0.1 microns and 10 microns. Barrier
coating 234 may cover all or part of drug-polymer coating 230, and
may cover all or part or stent framework 220.
[0037] FIG. 3 shows a schematic illustration of a drug-polymer
coating with at least one plasticizer interdispersed within the
drug-polymer coating, in accordance with one embodiment of the
present invention at 300. The pictorial illustration depicts a
drug-polymer coating 330, which includes polymer chains 334, drug
molecules 336, and at least one plasticizer 338 dispersed within
the drug-polymer coating.
[0038] Polymer chains 334 may comprise any suitable polymer chain
of small, medium or large molecular weights that can be less than
200 Daltons or exceed 500,000 Daltons. Polymeric chains 334 may be
amorphous, crystalline or a combination thereof. Polymeric chains
334 may comprise, for example, a linear polymer, a block copolymer,
or a polymer blend. Polymeric chains 334 may be networked or
cross-linked. Polymeric chains 334 may have a preferred
orientation, though are usually disposed randomly.
[0039] Drug molecules 336 are interdispersed within the
drug-polymer. The drugs typically have a smaller molecular weight
than the polymers, and may be mixed in with the polymers. The drugs
may be attached to the ends or grafted onto polymer chains 334 at
various sites along their length. Drug molecules 336 may include,
for example, various organic and pharmaceutical compounds that have
a therapeutic characteristic.
[0040] Plasticizers 338 comprise shorter, bulkier molecules.
Plasticizers 338 tend to separate polymer chains 334 from one
another, providing additional flexibility to the drug polymer.
Plasticizers 338 separate polymer chains 334 and can provide
additional locations for drug molecules 336 to reside. Examples of
plasticizers suitable for use in drug-polymer coatings include
lecithin, dibutyl sebacate, citric acid, an alcohol ester,
polyethylene glycol, polypropylene glycol, a biostable plasticizer,
a biocompatible plasticizer, a biodegradable plasticizer, or
combinations thereof.
[0041] Drug molecules 336 may be released from drug-polymer coating
330 by diffusing out from the coating, working their way through
the entanglement of polymer chains 334 until the surface of the
drug coating is reached, then furthering their discourse into the
blood stream or local tissue bed where they are metabolized or
otherwise absorbed into the body. Alternatively, dissolution of the
polymer chains can result in the release of drug molecules 336.
[0042] By tailoring the interdispersed plasticizers and drugs, the
concentration, distribution profile, and elution rates of bioactive
agents or drugs can be controlled. In one embodiment, a higher
concentration of plasticizers 338 are located closer to the stent
framework and away from the outer surface of the stent coating. In
this case, the release or elution of drug molecules 336 will tend
to be constant over a longer period of time. Alternatively, a
higher concentration of plasticizers 338 near the outer surface of
the stent coating will tend to result in a large initial burst of
drug. The distribution of the plasticizers and drugs can be
tailored to fit the desired elution rate by controlling the
concentration profile of the interdispersed plasticizers and
drugs.
[0043] FIG. 4 shows a graphical illustration of drug elution from a
drug-polymer coated stent including at least one plasticizer, in
accordance with one embodiment of the present invention at 400.
Elution graph 400 shows characteristic elution rate curves 410 and
420 for a drug being released from a stent coating. Drug elution
refers to the transfer of the bioactive agent out from the
drug-polymer coated stent. The elution rate is determined as the
amount of bioactive agent excreted out of the drug-polymer coating
per unit time, typically measured in units of weight such as
micrograms and units of time such as hours. In some cases, the
bioactive agent diffuses out of the drug-polymer coating. In other
cases, a portion of the polymeric coating is absorbed into the body
and bioactive agents are released. One of the ways of speeding the
transport of drug from the inner layers next to the stent framework
is through the addition of a suitable plasiticizer in the inner
layers of the stent coating. The release profile can be modulated
by tailoring the distribution of plasticizers and drugs within the
drug-polymer coating.
[0044] Elution rate curve 410 depicts an initially high elution
rate for the first couple of days and a rapidly decaying elution
rate over the next several weeks, for the case of a high
concentration of plasticizers near the outer surface of the drug
polymer.
[0045] Elution rate curve 420 depicts a flatter drug delivery rate,
for the case of a higher concentration of plasticizers near the
inner surface of the drug-polymer coating close to the stent
framework. Other profiles can be achieved by controlling the
distribution and concentration of the interdispersed drugs and
plasticizers in the stent coating.
[0046] Elution rate curve 430 avoids the burst effect altogether,
and has a more level elution rate over the first month. This
elution rate profile can be achieved, for example, with a low or
negligible concentration of drugs and plasticizers in a layer near
the outside of the stent coating, with a higher concentration of
drugs and plasticizers near the middle of the drug-polymer coating,
and a higher concentration yet in layers closest to the stent
framework.
[0047] FIG. 5 shows a flow diagram of a method of manufacturing a
drug-polymer coated stent, in accordance with one embodiment of the
present invention at 500. Manufacturing method 500 comprises
various steps to manufacture drug-polymer coated stents.
[0048] A polymeric material is mixed with a suitable solvent to
form a polymeric solution, as seen at block 510. The polymeric
material comprises, for example, a biostable polymer, biodegradable
polymer, or a biocompatible polymer for use on drug-polymer stents.
The polymeric material may include, for example, a linear polymer
such as polyethylene; a blocked copolymer such as a styrenic block
copolymer; a terpolymer such as poly(hexyl methacrylate), vinyl
acetate and vinyl pyrrolidinone; or a polymer blend such as
polycarbonate-polycaprolactone. The solvent may be any suitable
organic solvent capable of dissolving the polymeric material such
as chloroform, tetrahydrofuran, methyl chloride, toluene, ethyl
acetate, or dioxane.
[0049] One or more bioactive agents are mixed with the polymeric
solution to form a drug-polymer solution. The bioactive agents may
be added directly into the polymeric solution and mixed to form the
drug-polymer solution. Alternatively, the bioactive agents may be
dissolved in a bioactive agent solution comprising a suitable
solvent, then mixed with the polymeric solution to form the
drug-polymer solution. In either case, a suitable amount of
bioactive agent or drug is added to the drug-polymer solution.
Sufficient bioactive agents are added to achieve the desired
pharmaceutical intent when deployed. The drug constituency within
the drug-polymer coating is usually between 0.5 percent and 50
percent of the bioactive drug by weight.
[0050] A plasticizer is mixed and interdispersed within the
polymeric solution to form a plasticized drug-polymer coating, as
seen at block 520. The plasticizers may initially be in liquid or
solid form, and then mixed or dissolved in the polymeric solution.
The plasticizers may include, for example, lecithin, dibutyl
sebacate, citric acid, an alcohol ester, polyethylene glycol,
polypropylene glycol, a biostable plasticizer, a biocompatible
plasticizer, a biodegradable plasticizer, or a combination thereof.
The plasticizers may be added to the polymeric solution prior to or
after the addition of the bioactive agents.
[0051] An adhesion layer may be applied onto the stent framework,
as seen at block 530. The adhesion layer is applied prior to
applying the plasticized drug-polymer coating. The adhesion layer
includes a material such as, for example, parylene, polyurethane,
phenoxy, epoxy, polyimide, polysulfone, pellathane, a suitable
polymeric adhesion material, or a combination thereof. The stent
framework typically includes a metallic or a polymeric base. The
metallic base comprises a metal such as stainless steel, nitinol,
tantalum, MP35N alloy, platinum, titanium, a suitable biocompatible
alloy, a suitable biocompatible material, or any combination
thereof. The polymeric base is any suitable polymer for biomedical
stent applications, as is known in the art.
[0052] The plasticized drug-polymer coating is applied onto the
stent framework, as seen at block 540. The plasticized drug-polymer
coating may be applied using any suitable application technique
such as dipping, spraying, brushing, painting or dispensing.
[0053] The thickness of the plasticized drug-polymer coating can
vary, though is typically between 0.5 microns and 20 microns.
Depending on the diameter and length of the stent, the weight of
the plasticized drug-polymer coating is usually between 50
micrograms and 1500 micrograms for a range of stent sizes.
Additional coats may be added to thicken the plasticized drug
coating or to increase the drug dosage, if needed. Multiple coats
of the plasticized drug-polymer coating may be applied with varying
concentrations of plasticizers and various drugs, such that a
tailored plasticizer and drug profile can be attained to aid in the
control of the elution profile.
[0054] The plasticized drug-polymer coating is dried, as seen at
block 550. The plasticized drug-polymer coating may be dried for
example, by evaporating the solvent after application. The drying
may be performed at room temperature and under ambient conditions.
A nitrogen environment or other controlled environment may also be
used. Alternatively, the drug-polymer solution can be dried by
evaporating the majority of the solvent at room temperature, and
further dried in a vacuum environment between room temperature of
about 25 degrees centigrade and 45 degrees centigrade or higher to
extract any pockets of solvent buried within the drug-polymer
coating.
[0055] A barrier coating may be applied onto the plasticized
drug-polymer coating, as seen at block 560. The barrier coating
includes a material such as, for example, a polyurethane, a
phenoxy, ethylene vinyl acetate, polycaprolactone, polylactide,
fibrin, collagen, a biocompatible polymer, a biostable polymer, a
biodegradable polymer, or a combination thereof. The barrier
coating may be applied using any suitable application technique
such as dipping, spraying, brushing, painting or dispensing. The
barrier coating may be dried by heating the coated stent in a
vacuum or inert environment at an elevated temperature.
[0056] Additional drug-polymer coatings may be applied to the
plasticized drug-polymer coated stent. Additional barrier layers
may be positioned between the drug-polymer layers to aid in the
control of the elution rates of the incorporated drugs and
bioactive agents.
[0057] Variants of the method for manufacturing a drug-polymer
coated stent can be used, such as mixing the constituents into the
same solution, using different solvents for each component, or
altering the order of mixing stock solutions of each of the
constituents.
[0058] In one exemplary method, the coated stents are reduced in
diameter and placed into the distal end of the catheter. The
process forms an interference fit, which secures the stent onto the
catheter. The catheter with the stent may be placed in a catheter
package and sterilized prior to shipping and storing. Sterilization
of the stent using conventional procedures is completed typically
before clinical use.
[0059] When ready for deployment, the drug-polymer coated stent
including the bioactive agents and the grafted styrenic block
copolymer is inserted into a vessel of the body. The drug-polymer
coated stent is inserted typically in a controlled environment such
as a catheter lab or hospital. The stent is deployed, for example,
by expanding the stent with a balloon or by extracting a sheath to
allow a self-expandable stent to enlarge after positioning the
stent at the desired location within the body.
[0060] Once deployed, the drug-polymer coating elutes the bioactive
agents into the body and particularly into the tissue bed
surrounding the stent framework. The elution rates of the bioactive
agents into the body are based on the type of plasticizer and drugs
included in the plasticized drug-polymer coating, their
distribution profile, and other factors.
EXAMPLE 1 FORMULATION
[0061] In this example, details of one formulation for coating a
stent with a plasticized drug-polymer coating are described.
Initially, 0.0373 grams of an antirestonotic agent is weighed and
transferred into a small glass vial. An amount of polymeric
material comprising poly(butyl methacrylate-co-methyl
methacrylate), weighing 0.0448 grams, is transferred into the same
glass vial with the antirestonotic agent. One source of poly(butyl
methacrylate-co-methyl methacrylate) is provided by Sigma-Aldrich
Corporation, of St. Louis, Mo., catalog number 47403-7. An amount
of polybutylmethacrylate, weighing 0.0671 grams, is transferred
into the same glass vial with antirestonotic agent. Ten milliliters
of chloroform is added to the glass vial and the polymeric mixture
in the vial is shaken until all materials are dissolved. An amount
of dibutyl sebacate equal to 0.0134 grams is added to the vial and
shaken to get a uniform solution. The polymer solution is applied
onto a metallic stent, using a technique such as spraying. The
stent used in this example is an eighteen-millimeter long S670
stent made by Medtronic Ave, Santa Rosa, Calif. The plasticized
drug-polymer coating is then dried. The target weight of the
applied drug polymer, in this example, is 800 micrograms.
[0062] Although the present invention applies to cardiovascular and
endovascular stents with timed-release pharmaceutical drugs, the
use of plasticizers in polymer-drug coatings and other polymer
coatings may be applied to other implantable and blood-contacting
biomedical devices such as coated pacemaker leads, microdelivery
pumps, feeding and delivery catheters, heart valves, artificial
livers and other artificial organs.
[0063] While the embodiments of the invention disclosed herein are
presently considered to be preferred, various changes and
modifications can be made without departing from the spirit and
scope of the invention. The scope of the invention is indicated in
the appended claims, and all changes that come within the meaning
and range of equivalents are intended to be embraced therein.
* * * * *